1. Field of Invention
This invention relates to hyperthermia and immunotherapy for treatment of cancer.
2. Description of Prior Art
The earliest references to treating cancer with hyperthernia can be found in Egyptian papyrus scrolls dated back to 3000 BC describing a breast cancer patient treated with immersion in hot water. Total body hyperthermia in the form of hyperpyrexia (fever) has produced dramatic tumor regressions and even cures following infection with pyrogenic bacteria. In the late 19.sup.th and early 20.sup.th centuries Dr. William Coley reviewed cases of spontaneous tumor regression and discovered that a common factor was a prolonged fever in excess of 39.5 degrees C. or 103.5 degrees F.
Dr. Coley tried to duplicate the fevers with Streptococcus pyogenes bacterial lysates, which contained the pyrogenic material lipopolysaccharide (LPS). Coley treated a wide variety of carcinomas and sarcomas with his Mixed Bacterial Toxins (MBT), achieving 5-year survival rates of 60% in inoperable malignant melanoma cases. These rates are considerably higher than those obtained using surgery, radiation, and chemotherapy programs. Problems developed when patients began producing large quantities of neutralizing antibody which required larger amounts of MBT. In addition, Coley had difficulty standardizing the pyrogenicity of the toxins. Coley remained convinced that a key portion of his treatment's success was based due to the enhanced immune response to the toxins, which somehow was cross-reactive against the tumors. Current knowledge of immunology confirms Coley's hypothesis, but it is now clear that antiviral immunity is much more closely related to antitumor immunity than the antibacterial response mechanisms.
This is due to the fact that bacterial infections primarily stimulate the humoral or antibody+complement arm of the immune system. For extracellular parasites such as bacteria and protozoa, this provides an efficient means of elimination within the bloodstream. Viruses, however, are intracellular parasites, and virally-infected host cells express viral antigens on their cell surface in conjunction with normal cell proteins. Hence, Killer Lymphocytes, with ability to recognize and kill virally-infected cells are needed to eradicate the virus. Because cancerous cells also express "self" or normal host antigens on the cell surface along with "non-self" or mutated tumor antigens, the same effector cells: Natural Killer (NK), Lymphokine-Activated Killer (LAK), and antigen-specific Cytotoxic T Lymphocytes, have the primary responsibility of antitumor and antiviral surveillance and elimination. To date, there is no reference in the Scientific Literature to using a pyrogenic virus to induce whole-body hyperthermia.
Other techniques of inducing hyperthermia have been tried: immersion in hot liquids, limb perfusion, and even microwave radiation. The main disadvantage to these methods is that most cancers are deep within the tissue layers, and heating from the outside cannot generate a sufficient temperature to kill the tumor cells. Another problem with these prior-art approaches is that in metastasized cancer, tumor cells are spread throughout the body, and a treatment designed to be curative must heat the entire body as well. A whole-body pyremia approach utilizing a safe but pyrogenic virus solves these two difficulties.
Numerous versions of immunotherapy have been tried in cancer treatment, both specific and non-specific in nature. The primary non-specific immune modulator in cancer therapy has been Bacillus Calmette-Guerin, or BCG. BCG produces a Delayed-Type-Hypersensitivity (DTH) reaction which activates local macrophages to become tumorcidal in some cases. However, it is a poor pyrogenic agent, so hyperthermic benefits are not realized. Also, as detailed previously, it stimulates primarily the humoral arm of the immune system, so interferon production and NK activation are generally low.
Exogenous interferon therapies have been attempted, but suffer from purification and toxicity problems. Researchers have been able to achieve alpha-interferon levels 10 times greater than normal, but the response is hampered by Serum Blocking Factors (SBF) which neutralize the foreign interferon before it can induce a strong cellular response. Immunologists are in general agreement that therapies which stimulate endogenous interferon production are preferable to those which rely on injection of recombinant interferons and interleukins. The described immunotherapy stimulates endogenous interferon A levels approximately 260 times normal levels.
Numerous approaches to cancer vaccines have been attempted, with both sub-unit peptide and whole cell irradiated preparations generating a measurable response. In the case of malignant melanoma, polypeptide vaccines containing a common melanoma antigen: gp100, MART-1/Melan-A, and TRP-1, (Tyrosinase-Related Protein), have been clinically tested. The major drawback to these approaches is that being polypeptides, they provoke a stronger antibody that Killer Cell response. In addition, not all melanoma cells express these antigens in vivo to label them for identification and lysis by effector cells.
Another antigen-specific approach is to use whole cancer cells which have been killed in a manner (usually irradiation) that leaves their antigenic structure intact. These cells are then injected back into the body to induce an immune response. The problem with this approach is that the tumor burden must be reduced by physical means before the specific Cytotoxic T Lymphocytes are induced. The three major anticancer therapies: surgery, radiation, and chemotherapy reduce tumor burden but simultaneously devastate the immune system. The described immunotherapy solves this major problem.